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United States Patent |
5,191,076
|
Saito
,   et al.
|
March 2, 1993
|
Acetyloxylation process for producing 4-acetoxyazetidinones with osmium
catalyst
Abstract
A process for producing a 4-acetoxyazetidinone represented by formula (I):
##STR1##
wherein Z represents a hydrogen atom, a lower alkyl group, or a protected
or unprotected hydroxyethyl group; and W represents a hydrogen atom, a
lower alkyl group, or a group of --COOR.sup.1, wherein R.sup.1 represents
a lower alkyl group, is disclosed, which comprises reacting an azetidinone
represented by formula (II):
##STR2##
wherein Z is as defined above; and Y represents a hydrogen atom, carboxyl
group, a lower alkyl group, or a group of --COOR.sup.1, wherein R.sup.1
represents a lower alkyl group, with acetic acid and an oxidizing agent in
the presence of, as a catalyst, an anhydrous or hydrous osmium compound
represented by OsX.sub.3, wherein X represents a chlorine atom, a bromine
atom, or an iodine atom.
Inventors:
|
Saito; Takao (Tokyo, JP);
Kumobayashi; Hidenori (Tokyo, JP);
Murahashi; Shunichi (Tokyo, JP)
|
Assignee:
|
Takasago International Corporation (Tokyo, JP)
|
Appl. No.:
|
799150 |
Filed:
|
November 26, 1991 |
Foreign Application Priority Data
Current U.S. Class: |
540/357 |
Intern'l Class: |
C07D 205/08; C07B 041/12 |
Field of Search: |
540/357
|
References Cited
Foreign Patent Documents |
0180252 | May., 1986 | EP.
| |
0290385 | Nov., 1988 | EP.
| |
0371875 | Jun., 1990 | EP.
| |
Other References
Braun et al, TCS Chem Comm 1972, p. 229.
Murahashi, Tetrahedron Letters, vol. 32, No. 19, pp. 2145-2148 (1991).
|
Primary Examiner: Berch; Mark L.
Attorney, Agent or Firm: Sughrue, Mion, Zinn, Macpeak & Seas
Claims
What is claimed is:
1. A process for producing a 4-acetoxyazetidinone represented by formula
(I):
##STR18##
wherein Z represents a hydrogen atom, a lower alkyl group, or a protected
or unprotected hydroxyethyl group; and W represents a hydrogen atom, a
lower alkyl group, or a group of the formula --COOR.sup.1, wherein R.sup.1
represents a lower alkyl group, which comprises reacting an azetidinone
represented by the formula (II):
##STR19##
wherein Z is as defined above; and Y represents a hydrogen atom, a
carboxyl group, a lower alkyl group, or a group of the formula
--COOR.sup.1, wherein R.sup.1 represents a lower alkyl group, with acetic
acid and an oxidizing agent in the presence of, as a catalyst, an
anhydrous or hydrous osmium compound represented by the formula OsX.sub.3
or hydrated versions thereof, wherein X represents a chlorine atom, a
bromine atom, or an iodine atom, with the proviso that when Y represents a
hydrogen atom, a lower alkyl group, or --COOR.sup.1, then W represents Y,
and when Y represents --COOH, then W represents a hydrogen atom.
2. A process as in claim 1, wherein said oxidizing agent is peracetic acid.
3. A process as in claim 1, wherein said osmium compound is osmium
trichloride.
4. A process as in claim 1, wherein the reaction is carried out with at a
temperature of from -10.degree. C. to 50.degree. C. for from 10 minutes to
5 hours.
5. A process as in claim 1, wherein acetic acid is used in an amount of
from 10 to 60 mole per mole of said azetidinone represented by formula
(II).
6. A process as in claim 1, wherein said oxidizing agent is used in an
amount of from 1 to 8 mole per mole of said azetidinone represented by
formula (II).
7. A process as in claim 1, wherein said osmium compound is used in an
amount of from 0.001 to 0.05 mole per mole of said azetidinone represented
by formula (II).
8. A process as in claim 1, wherein the reaction is carried out in the
further presence of an acetic acid salt.
Description
FIELD OF THE INVENTION
The present invention relates to a process for producing an intermediate
useful for synthesis of penem antibiotics represented by thienamycin. More
particularly, the present invention relates to a process for producing a
4-acetoxyazetidinone derivative represented by formula (I):
##STR3##
wherein Z represents a hydrogen atom, a lower alkyl group, or a protected
or unprotected hydroxyethyl group; and W represents a hydrogen atom, a
lower alkyl group, or a group of --COOR.sup.1, wherein R.sup.1 represents
a lower alkyl group.
BACKGROUND OF THE INVENTION
Since penem antibiotics represented by thienamycin have a broad
antibacterial spectrum, they are being watched with keen interest as
medicines.
Various processes for producing penem antibiotics have been proposed in,
for example, Kametani, Heterocycles, 17, pp. 463-506 (1982) and Shibuya,
Yuki Gosei Kauaku, 41, p. 62 (1983). Of these, the processes in which the
desired antibiotics are synthesized via 4-acetoxyazetidinone derivatives
represented by formula (I) as intermediates are advantageous in that
various penem antibiotics can be produced because compounds (I) can react
with a variety of nucleophilic agents.
Conventionally known methods for producing 4-acetoxy-azetidinone
derivatives (I) include oxidation of a 4-carboxy-azetidinone with lead
tetraacetate [Tetrahedron Letters, 23, p. 2293 (1982)], electrolytic
oxidation of a 4-carboxyazetidinone [Tetrahedron Letters, 29, p. 1409
(1988)], oxidation of a 4-acetylazetidinone with m-chloroperbenzoic acid
(JP-A-61-50964) (the term "JP-A" as used herein means an "unexamined
published Japanese patent application"}, and treatment of a
4-silyloxy-azetidinone derivative with acetic anhydride (European Patent
247,378).
In the above methods, in order to introduce an acetoxy group at the
4-position of the azetidinone, an azetidinone derivative having a specific
substituent group at the 4-position thereof should first be synthesized,
and an acetoxy group should be then introduced by converting this
substituent group. However, these methods are defective in that not only
the production of such an azetidinone derivative having a specific
substituent group at the 4-position thereof is troublesome, but the
conversion of the substituent group at the 4-position into an acetoxy
group is difficult. For these reasons, the above methods have been
unavoidably disadvantageous as an industrial method.
As an expedient for eliminating the above-described drawbacks, it has been
proposed to introduce an acetoxy group into an azetidinone at the
4-position thereof by use of a ruthenium compound (JP-A-2-231471).
However, in industrialization of this method, further improvements in
catalytic activity have been desired.
SUMMARY OF THE INVENTION
Under these circumstances, the present inventors have made intensive
studies. As a result, it has now been found that by reacting an
azetidinone with acetic acid and an oxidizing agent in the presence of an
osmium compound as a catalyst, an acetoxy group can be easily introduced
into the azetidinone at the 4-position thereof and the catalytic activity
is higher than that in a method employing a ruthenium compound as a
catalyst. The present invention has been completed based on this finding.
Accordingly, an object of the present invention is to provide a process for
producing a 4-acetoxyazetidinone represented by formula (I):
##STR4##
wherein Z represents a hydrogen atom, a lower alkyl group, or a protected
or unprotected hydroxyethyl group; and W represents a hydrogen atom, a
lower alkyl group, or a group of --COOR.sup.1, wherein R.sup.1 represents
a lower alkyl group, which comprises reacting an azetidinone represented
by formula (II):
##STR5##
wherein Z is as defined above; and Y represents a hydrogen atom, carboxyl
group, a lower alkyl group, or a group of --COOR.sup.1, wherein R
represents a lower alkyl group, with acetic acid and an oxidizing agent in
the presence of, as a catalyst, an anhydrous or hydrous osmium compound
represented by OsX.sub.3, wherein X represents a chlorine atom, a bromine
atom, or an iodine atom.
DETAILED DESCRIPTION OF THE INVENTION
The alkyl moiety in the lower alkyl group or lower alkoxy group as referred
to in the present invention preferably has from 1 to 4 carbon atoms.
Examples of the azetidinone (II) which is used as a raw material in the
present invention include azetidin-2-one, 3-methylazetidin-2-one,
3-ethylazetidin-2-one, 3-hydroxyethylazetidin-2-one,
3-methyl-4-carboxyazetidin-2-one, 3-ethyl-4-carboxyazetidin-2-one,
3-(protected) hydroxyethyl-4-carboxyazetidin- 2-one,
4-methylazetidin2-one, and 4-methoxycarbonylazetidin-2-one.
As the protective group of the hydroxyl group, those which are generally
used for protection of hydroxyl group in lactam compounds can be used.
Examples thereof include silyl groups (e.g., trimethylsilyl,
triethylsilyl, tert-butyldi-methylsilyl, and diphenyl-tert-butylsilyl), a
benzyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group, and an
o-nitrobenzyl-oxycarbonyl group.
Of the above-enumerated azetidinone derivatives (II), a compound in which Z
is a (protected) hydroxyethyl group, and Y is hydrogen atom can be
produced from a compound of formula (III) which is derived, for example,
from acetoacetic acid Ber., 92, p. 1599 (1959)], according to the
following reaction scheme.
##STR6##
In the above reaction scheme, R.sup.2 represents a protective group of a
carboxylic acid; R.sup.3 represents a hydrogen atom, a lower alkyl group,
a lower alkoxy group, or a phenyl or benzyloxy group which may be
substituted with a lower alkyl group or a lower alkoxy group; and R.sup.4
represents a protective group of a hydroxyl group.
That is, compound (III) is subjected to enantio-selective hydrogenation
using a ruthenium-optically active phosphine complex as a catalyst to give
compound (IV), which is then hydrolyzed with a dilute acid, etc. into
compound (V). Compound (V) is neutralized to give compound (VI), which is
then lactamization to obtain compound (II-1). Subsequently, the hydroxyl
group of this compound (II-1) is protected to give compound (II-2).
Examples of the osmium compound used as a catalyst in the present invention
are anhydrous or hydrous osmium tri-chloride, osmium tribromide, and
osmium triiodide. Of these, osmium trichloride is particularly preferred.
The oxidizing agent used in the present invention is not especially
limited. Examples thereof include peroxides of various carboxylic acids,
other peroxides, high-concentration bleaching powder, ozone, cyclohexene
ozonide, sodium peroxide, sodium perborate, iodosylbenzene diacetate,
iodosylbenzene, sodium metaperiodate, and sodium paraperiodate. Specific
examples of the carboxylic acid peroxides include peracetic acid,
perpropionic acid, and m-chloroperbenzoic acid. These compounds may be
ones which are commercially available, or they may be prepared separately
from a carboxylic acid and hydrogen peroxide before the reaction. Further,
specific examples of other peroxides include methyl ethyl ketone peroxide,
methyl isobutyl ketone peroxide, cyclohexanone peroxide,
methyl-cyclohexanone peroxide, diacetyl peroxide, dipropionyl peroxide,
and diisobutyryl peroxide. Use of peracetic acid as the oxidizing agent is
advantageous in that it is not particularly required to add acetic acid to
the reaction system because acetic acid is usually incorporated in
peracetic acid.
It is preferred in the present invention to conduct the reaction with
acetic acid in the presence of an acetic acid salt, since the presence of
an acetic acid salt results in an improved yield. Examples of the acetic
acid salt include sodium acetate, potassium acetate, and lithium acetate.
The present invention can, for example, be practiced as follows. Compound
(II), an oxidizing agent, acetic acid, and an osmium compound are
dissolved or suspended in a suitable solvent, and the solution or
suspension is reacted with stirring at a temperature of -10.degree. C. to
50.degree. C. for from 10 minutes to 5 hours, and preferably about 2
hours. The addition order and method of the raw material compound,
catalyst, and other ingredients are not particularly limited. It is,
however, desirable that the oxidizing agent be added gradually after all
the other ingredients.
As the solvent, organic solvents such as acetonitrile, methylene chloride,
acetone, acetic acid, and acetic acid esters can be used. The amount of
acetic acid used is preferably from 10 to 60 mole, and more preferably
from 20 to 40 mole, per mole of compound (II), while the amount of the
oxidizing agent used is preferably from 1 to 8 mole, and more preferably
from 2 to 3 mole, per mole of compound (II). The amount of the osmium
compound which is used as a catalyst is preferably from 0.001 to 0.05
mole, and more preferably from 0.01 to 0.03 mole, per mole of compound
(II).
Isolation of the desired compound from the resulting reaction mixture can
be accomplished by a known means such as, for example, recrystallization
and column chromatography.
The process of the present invention is more advantageous in efficiently
obtaining a 4-acetoxyazetidinone derivative than the above-described
method employing a ruthenium compound as a catalyst. That is, in the
conventional method employing a ruthenium compound as a catalyst, the
ruthenium compound should be used in an amount as large as about 10 mole %
of the substrate azetidinone, whereas in the present invention, a
4-acetoxyazetidinone can be obtained in good yield as long as the osmium
compound is used even in an amount as small as about 2 mole % of the
substrate.
The compounds obtained by the process of the present invention are
industrially useful compounds. Of these,
(1',R,3R,4R)-4-acetoxy-3-(1'-tert-butyldimethylsilyloxy)-ethylazetidin-2-o
ne of the formula:
##STR7##
wherein t-Bu is a tert-butyl group; and Ac is an acetyl group, is a
particularly useful intermediate indispensable for syntheses of
thienamycin and other important penem antibiotics. According to the
present invention, this compound can be obtained at a diastereomer
selectivity of 99% or more.
As described above, the process of the present invention can produce
4-acetoxyazetidinone derivatives (I) useful as intermediates for synthesis
of penem antibiotics by simple procedures with good catalytic activity
and, hence, is an industrially advantageous process.
The present invention will be explained below in more detail with reference
to the following examples, which should not be construed to be limiting
the scope of the invention.
EXAMPLE 1
Synthesis of 4-Acetoxyazetidin-2-one
To a mixture of 200 mg (2.8 mmole) of azetidin-2-one, 230 mg (2.8 mmole) of
anhydrous sodium acetate, 2 ml of acetic acid, and 17 mg (2 mole % based
on the amount of azetidin-2-one) of osmium trichloride trihydrate was
added dropwise, with stirring, 1.56 g (6.2 mmole) of a 30% peracetic acid
solution in ethyl acetate at room temperature over a period of 2 hours or
more. The reaction mixture was poured into 50 ml of water and extracted
with n-hexane. The extract was separated and purified by silica gel column
chromatography (n-hexane/ethyl acetate=1/1 by volume). Thus, 280 mg (2.2
mmole, percent yield: 78%) of 4-acetoxyazetidin-2-one in a colorless oily
state was obtained.
EXAMPLES 2 TO 6
The same procedures as in Example 1 were repeated except that the substrate
azetidinone and the amount (mole %) of osmium trichloride trihydrate
relative to the amount of the substrate were changed as shown in Table 1.
As a result, the 4-acetoxyazetidinones as shown in Table 1 were obtained
from the respective substrates in respective percent yields shown in the
same table.
TABLE 1
__________________________________________________________________________
Ex. Synthesized 4- OsCl.sub.3.3H.sub.2 O
Percent
No.
Substrate Acetoxyazetidinone (mol %)
Yield (%)
__________________________________________________________________________
##STR8##
##STR9## 2 76
3
##STR10##
##STR11## 2 43
4
##STR12##
##STR13## 2 92
5
##STR14##
##STR15## 2 77
6
##STR16##
##STR17## 2 48
__________________________________________________________________________
EXAMPLES 7 TO 11
Synthesis of
(1'R,3R,4R)-4-Acetoxy-3-(1'-tert-butyldimethyl-silyloxy)ethylazetidin-2-on
To a mixture of 200 mg (0.87 mmole) of
(1'R,3S)-3-(1'-tert-butyldimethylsilyloxy)ethylazetidin-2one, 72 mg (0.87
mmole) of anhydrous sodium acetate, 2 ml of acetic acid, and 7 mg of
osmium trichloride trihydrate was added dropwise, with stirring, 1.91
mmole of each of the oxidizing agents as shown in Table 2 at room
temperature over a period of 2 hours or more. (The oxidizing agents were
used as they were or in the form of a methylene chloride solution.) Each
of the reaction mixtures was poured into 50 ml of water and extracted with
n-hexane. The extract was distilled in vacuo and separated and purified by
silica gel column chromatography (n-hexane/ethyl acetate=8/1 by volume).
Thus,
(1'R,3R,4R)-4-acetoxy-3-(1'-tert-butyldimethylsilyloxy)ethylazetidin-2-one
was obtained in a percent yield shown in Table 2.
TABLE 2
______________________________________
Example Oxidizing OsCl.sub.3.3H.sub.2 O
Percent
No. Agent (mole %) Yield (%)
______________________________________
7 CH.sub.3 CO.sub.3 H
2.3 92
8 mCPBA.sup.1) 2.3 73
9 PhI(OAc).sub.2.sup.2)
2.3 70
10 PhIO.sup.3) 2.3 67
11 MEKP.sup.4) 2.3 70
______________________________________
.sup.1) : mchloroperbenzoic acid
.sup.2) : iodosylbenzene diacetate
.sup.3) : iodosylbenzene
.sup.4) : methyl ethyl ketone peroxide
EXAMPLE 12
Synthesis of 4-Acetoxy-3-ethylazetidin-2-one
To a solution prepared by mixing 500 mg (5 mmole) of 3-ethylazetidin-2-one,
415 mg (5 mmole) of anhydrous sodium acetate, 5 ml of acetic acid, and 30
mg (abut 2 mole % based on the amount of 3-ethylazetidin-2-one) of osmium
trichloride trihydrate was added dropwise, with stirring , 2.8 g (11
mmole) of a 30% peracetic acid solution in ethyl acetate at room
temperature over a period of 2 hours or more. The reaction mixture was
further stirred at room temperature for 4 hours, subsequently poured into
80 ml of water, and then extracted thrice with 100 ml of hexane. The
extract was dried over anhydrous magnesium sulfate, and the solvent was
removed by evaporation under reduced pressure. The residue was separated
and purified by silica gel column chromatography (n-hexane/ethyl
acetate=1/1 by volume). Thus, 780 mg of 4-acetoxy-3-ethylazetidin-2-one
was obtained. The percent yield was 78%.
.sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 0.99 (3H, t, J=7.4 Hz), 1.75 (2H,
m), 2.10 (3H, s), 3.08 (1H, m), 5.78 (1H, d, J=1.25 Hz), 6.55 (1H, b, NH)
While the invention has been described in detail and with reference to
specific embodiments thereof, it will be apparent to one skilled in the
art that various changes and modifications can be made therein without
departing from the spirit and scope thereof.
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